Topical pharmaceutical formulation

ABSTRACT

A composition comprising a non-volatile silicone fluid in admixture with fumed silica and a pharmaceutical active agent.

The present invention relates to silicone based compositions, a methodof manufacturing such compositions and the use of such compositions inmedicine. In particular, although not exclusively, the present inventionprovides a silicone based wound dressing comprising a pharmaceuticalactive agent for the curative and/or prophylactic treatment of a medicalcondition.

Damage to the skin, for example produced by injury or surgery, mayproduce wounds which are susceptible to infection by pathogens, such asviruses and bacteria. Suitably, it may be necessary to treat such woundswith one or more pharmaceutical active agents, such as an antibiotic,anti-viral and/or antifungal compound in the hope of alleviating orpreventing infection of the wound. Although such pharmaceutical activeagents may be administered by various routes, such as oral or topicaladministration, topical administration of the active agent represents aconvenient and effective mode of administration for the patient.

Although, pharmaceutical gel and cream formulations for delivering atherapeutic effective amount of a drug to a target tissue by topicaladministration are known, the universal applicability of theseformulations to treat a particular target tissue site, in particular awound, may be restricted for a number of reasons. In particular, topicalpharmaceutical preparations may require complex formulations so that atherapeutic effective amount of the pharmaceutical active agent isdelivered to the target tissue (for example wounds, cuts or skinlesions) whilst minimising undesirable side effects, such as irritationof the skin and mucosa. Complex formulations may also be required toprevent degradation of the active agent in the formulation and/orminimise physical instability of the formulation itself (e.g. separationof the component parts, thickening precipitation/agglomerization of theactive agent). Such problems may be further enhanced when thepharmaceutical active agent is a solid that is substantially in solublein common pharmaceutical diluents/carriers etc. Suitably, such solidpharmaceutical active agents may necessitate particularly complexformulations. A still further potential problem with known topicalpharmaceutical formulations which may render them unsuitable forapplication to a wound, such as skin lesion or cut, is that suchformulations may prevent normal skin function, they may suppress thenormal immune response and they may allow pathogens, such as bacteria,to evolve around the barriers which they provide.

In addition to the likelihood of infection, damage to the skin producedby injury or surgery may produce scars instead of regenerating theoriginal tissue. Such scars are typically undesirable as they may createembarrassing cosmetic problems and the scar tissue typically lacks thefunctionality of normal skin. For example, the sense of touch may bediminished or completely lost and weak spots may form where the scartissue joins uninjured tissue. Suitably, a wound dressing adapted toreduce, prevent and/or ameliorate scar formation may be applied to thetarget tissue or scar, respectively.

Typically, treatment regimes for reducing or preventing infection of awound include the application of an antibiotic formulation, for examplean antibiotic ointment, to the wound followed by the application of acovering, such as a bandage, to enhance contact of the ointment aroundthe wound. Suitably, these coverings may include an adhesive forretaining the covering in position. Unfortunately, the presence of anadhesive may cause an allergic reaction which may negatively effect thehealing process.

In order to prevent or reduce infection and/or scar formation of a woundit is usually necessary to apply a separate pharmaceutical active agent,such as an antibiotic ointment, and thereafter a wound dressing orcovering designed to reduce or prevent scar formation. A problemassociated with such treatment methods is that the regime involves twosteps; the application of the antibiotic followed by the separateapplication of the wound dressing or covering. Suitably, if it isnecessary to apply a further amount of the pharmaceutical active agentto the wounded tissue, then the wound dressing will have to be removedand the above two steps repeated. Inconveniently, this may not onlyreduce patient compliance but may inflict further damage to the injuredtissue and further pain to the patient.

The present invention therefore seeks to provide improved compositionssuitable for application to a target tissue site, in particular a targettissue site that it is susceptible to pathogenic infection and/orscarring, especially to a skin lesion or wound.

According to a first aspect, the present invention provides acomposition comprising a non-volatile silicone fluid in admixture withfumed silica, and a pharmaceutical active agent. Such a composition isreferred to hereinafter as the composition of the present invention.

Suitably, the composition of the present invention seeks to solve theaforementioned technical problems associated with treating a wound. Inparticular, the mixture of the non-volatile silicone fluid and fumedsilica in the composition of the present invention may act as a suitablevehicle to permit a therapeutic effective amount of the pharmaceuticalactive agent to be delivered to and retained by a target tissue site(i.e. skin lesion or cut). Suitably, the pharmaceutical active agentdoes not degrade and typically exhibits physical stability in thecomposition of the present invention. For example, the components of thecomposition may not separate and the pharmaceutical active agent may notprecipitate/agglomerize. Suitably, the composition of the presentinvention does not require an additional adhesive to retain it inposition on the target tissue site, thereby minimising allergicreactions which may negatively effect the healing process.

Suitably, the composition of the present invention is dual purpose as itmay be used as a wound dressing to reduce, prevent or amelioratescarring of damaged tissue and/or it also may be used for the topicaldelivery of a pharmaceutical active agent to the tissue. Consequently,the composition of the present invention enables a pharmaceutical activeagent and a wound dressing/covering to be applied to a target tissue ina single step thereby increasing patient compliance compared with a twostep regime which involves the separate application of a pharmaceuticalactive agent followed by application of a separate wound dressing. Itwill be appreciated that the composition of the present invention may beapplied by medical and non-medical professional staff, as it isstraightforward to apply. Such methods of application by non-medicalprofessional staff are embraced by the methods of the present inventionas described hereinafter.

Suitably, the composition of the present invention may negate the needfor a complex formulation of the pharmaceutical active agent to ensurethat a therapeutic effective amount of the active agent is delivered tothe target tissue when the patient moves, as the blend of thenon-volatile silicone fluid and the fumed silica typically acts as acarrier for the pharmaceutical active agent and typically has a suitableviscosity to adhere to the target tissue.

Suitably, the activity of the pharmaceutical active agent in thecomposition of the present invention may be enhanced compared toemploying the unmodified pharmaceutical active agent alone. Moreover,pharmaceutical active agents in the form of powders and liquids, may beused in the composition of the present invention without the need forfurther processing. Consequently, the composition of the presentinvention may overcome problems associated with delivering a therapeuticeffective amount of a liquid or solid pharmaceutical active agent to atarget tissue (i.e. delivering and retaining the active agent at thetarget site for sufficient time to enable the active agent to have thedesired effect) whilst increasing the efficacy of the active agent.

Suitably, the composition of the present invention may exhibit increasedreduction and/or prevention of scars when applied to a target tissue(i.e. wound) compared to a substantially identical composition notincluding the pharmaceutical active agent.

As mentioned previously, pharmaceutical active agents in the form of apowder or liquid themselves, particularly a powder, typically requirecomplex formulations so that they may be applied topically to a targettissue site. Moreover, a separate cover, such as a wound dressing, istypically required to retain the pharmaceutical active agent at thetarget tissue site. For example, as a powder is very fragile and easilyremoved from the skin an adhesive plaster is usually used to retain thepowder, or a formulation thereof, at the target site. However, theadhesive may irritate the target site and the process of normal skinactivity may also be impaired i.e. it may prevent the skin from allowingthe passage of water vapour, gases and toxins therefrom. Although onlytheory, it is believed that any increased efficacy of a pharmaceuticalactive agent, such as an antibacterial agent, when incorporated in amixture of non-volatile silicone fluid and fumed silica may not only bedue to the mixture of non-volatile silicone fluid and fumed silicaretaining and delivering the active agent to the target tissue site butalso may be due to the mixture of non-volatile silicone fluid and fumedsilica allowing the target site (i.e. skin) to function normally. Inparticular, although the mixture of non-volatile silicone fluid andfumed silica in itself does not appear to possess antibacterialactivity, it is believed that when it is applied to the skin it providesa barrier to potential pathogens and because it is hydrophobic it allowsthe skin to function normally i.e. it permits the passage of watervapour, gases and toxins therefrom, thereby enhancing the effect of thepharmaceutical active agent. Suitably, the composition of the presentinvention may possess antibacterial, antiviral and/or antifungalactivity. Suitably, the composition of the present invention may promotenormal skin function without suppressing the normal immune response.Suitably, the composition of the present invention may not irritate thetarget tissue. Still further, the composition of the present inventiontypically does not require professional attention for propermaintenance, particularly for a minor wound.

By the term “non-volatile silicone fluid” we include a silicone fluidthat does not substantially evaporate from the composition of thepresent invention at normal body temperature (i.e. up to and including38° C.) and atmospheric pressure. Preferably, the non-volatile siliconefluid does not substantially evaporate from the composition at roomtemperature (i.e. up to and including 25° C.) and at atmosphericpressure.

Suitably, the non-volatile silicone fluid per se does not exhibit anappreciable vapour pressure at ambient temperature. Preferably, thevolatile content of the non-volatile silicone fluid per se at 150° C. isless than or equal to 0.8% by weight, more preferably less than or equalto 0.6% by weight, even more preferably less than or equal to 0.4% byweight, most preferably less than or equal to 0.3% by weight based onthe total weight of the non-volatile silicone fluid per se.

Suitably, the non-volatile silicone fluid component forms the base forthe composition of the present invention and provides the chemicalproperties of the barrier between the injured target tissue and theenvironment. Suitably, the non-volatile silicone fluid is a siliconepolymer.

Preferably, the non-volatile silicone fluid is a non-volatile siliconeoil. Preferably, the non-volatile silicone fluid has a viscosity at 25°C. of greater than or equal to 500 centistokes, more preferably greaterthan or equal to 5,000 centistokes, most preferably greater than orequal to 10,000 centistokes when measured by ASTM D-445, IP71 using aglass capillary viscometer such as an Ubbelohde available from FisherScientific Co., Pittsburgh, Pa., USA. Preferably, the silicone fluid hasa viscosity at 25° C. of less than or equal to 200,000 centistokes, morepreferably less than or equal to 100,000 centistokes, most preferablyless than or equal to 50,000 centistokes. Suitably, viscosities up to100,000 centistokes may be measured by ASTM D-45, IP71 using a glasscapillary viscometer. Viscosities above 100,000 centistokes may bemeasured using rotational viscometers such as a BrookfieldSynchro-lectric viscometer or a Wells-Brookfield Core/Plate viscometeravailable from Brookfield Engineering Laboratories, Stoughton, Mass.,USA employing test methods ASTM D-1084 (for a cup/spindle viscometer)and ASTM D-4287 (for a cone/plate viscometer). Suitably, when measuringviscosities above 100,000 centistokes, viscometers designed for the highviscosity region (HA and HB models) are employed. Highly preferrednon-volatile silicone fluids have a viscosity at 25° C. of about 30,000centistokes when measured by ASTM D-445, IP71 using a glass capillaryviscometer.

Preferably, the non-volatile silicone fluid comprises a siliconepolymer, particularly a linear silicone polymer, especially a lineardimethicone polymer. Highly preferred non-volatile silicone fluidscomprise a polydimethyl-siloxane polymer, especially a linearpolydimethylsiloxane polymer.

It will be appreciated that by increasing the viscosity of thenon-volatile silicone fluid in the composition of the invention mayproduce a composition having increased durability and resistance toremoval from the target tissue site, particularly following evaporationof the volatile diluent as described hereinafter from the composition ifone is used. Similarly, by lowering the viscosity of the non-volatilesilicone fluid component produces a composition which may be more easilyapplied to and removed from the target tissue. By using the full rangeof silicone oil viscosities, the composition of the present inventionmay be tailored to the unique needs of each case. Silicone fluids havingviscosities at 25° C. of about 30,000 centistokes are especiallypreferred as they provide a balance of residual durability and ease ofapplicability. A particularly preferred non-volatile silicone fluid isDow Corning 200 having a viscosity at 25° C. of about 30,000 centistokesproduced by Dow Corning Inc. (Midland, Mich.).

Preferably, the non-volatile silicone fluid is present in an amount ofgreater than or equal to 20% by weight, more preferably greater than orequal to 30% by weight, even more preferably greater than or equal to40% by weight, even more preferably greater than or equal to 50% byweight, even more preferably greater than or equal to 60% by weight,even more preferably greater than or equal to 70% by weight, even morepreferably greater than or equal to 80% by weight, even more preferablygreater than or equal to 85% by weight, most preferably greater than orequal to 90% by weight based on the total weight of the composition ofthe present invention. Preferably, the non-volatile silicone fluid ispresent in an amount of less than or equal to 99% by weight, morepreferably less than or equal to 97% by weight, even more preferablyless than or equal to 95% by weight based on the total weight of thecomposition of the present invention.

Suitably, the fumed silica provides a micro-skeletal structure whendispersed in the non-volatile silicone fluid to provide a gel.Preferably, the fumed silica is amorphous. The viscosity of the originalnon-volatile silicone fluid may be dramatically increased when mixed(e.g. blended) with suitable quantities of fumed silica to form, forexample a non-fluid grease-like gel. Any amorphous fumed silica thatsuitably thickens the non-volatile silicone fluid component may be used.Such fumed silicas include both untreated types and types that have beenchemically treated to alter the fumed silica surface. Examples ofsuitable fumed silicas include but are not limited to Aerosil™ 90, 130,200, 300, 380, R202, R805, R812, R972, R974 (Degussa Corporation,Ridgefield Park, N.J.) and CAB-O-SIL™ TS-720 and M-5 (Cabot Corporation,Tuscola, Ill.). Generally, Aerosil™ 200, Aerosil™ R974, CAB-O-SIL™TS-720 and any other generally equivalent products from othermanufacturers of fumed silicas are preferred as they suitably thickennon-volatile silicone fluids. Typically, the larger the quantity offumed silica in the blend, the more viscous is the resultant gel.

Preferably, the fumed silica is present in an amount of greater than orequal to 0.25% by weight, more preferably greater than or equal to 0.5%by weight, even more preferably greater than or equal to 1% by weight,most preferably greater than or equal to 2% by weight based on the totalweight of the composition of the present invention. Preferably, thefumed silica is present in an amount of less than or equal to 10% byweight, more preferably less than or equal to 8% by weight, even morepreferably less than or equal to 6% by weight, most preferably less thanor equal to 5% by weight based on the total weight of the composition ofthe present invention. A particularly preferred composition of thepresent invention comprises approximately 3% by weight fumed silicabased on the total weight of the composition of the present invention.

Preferably, in the composition of the present invention the blend ofnon-volatile silicone fluid and fumed silica comprises from greater thanor equal to 0.25%, more preferably greater than or equal to 0.5%, mostpreferably greater than or equal to 1% by weight fumed silica.Preferably, in the composition of the present invention the blend ofnon-volatile silicone fluid and fumed silica comprises less than orequal to 12%, more preferably less than or equal to 9%, most preferablyless than or equal to 5% by weight fumed silica. Such compositionstypically provide a balance of thickness and workability.

Preferably, in the composition of the present invention the blend ofnon-volatile silicone fluid and fumed silica comprises from less than orequal to 99.75%, more preferably less than or equal to 99.5%, mostpreferably less than or equal to 99% by weight non-volatile siliconefluid. Preferably, in the composition of the present invention the blendof non-volatile silicone fluid and fumed silica comprises greater thanor equal to 88%, more preferably greater than or equal to 91%, mostpreferably greater than or equal to 95% by weight non-volatile siliconefluid.

Preferably, in the composition of the present invention the blend of thenon-volatile silicone fluid and fumed silica is present in an amount ofgreater than or equal to 1%, preferably greater than or equal to 22%,preferably greater than or equal to 24.9%, preferably greater than orequal to 47%, preferably greater than or equal to 49.9%, preferablygreater than or equal to 57%, preferably greater than or equal to 59.9%,preferably greater than or equal to 62%, preferably greater than orequal to 64.9% by weight of the composition of the present invention.Preferably, in the composition of the present invention the blend of thenon-volatile silicone fluid and fumed silica is present in an amount ofless than or equal to 98.9%, preferably less than or equal to 96%,preferably less than or equal to 94.9%, preferably less than or equal to92%, preferably less than or equal to 89.9%, preferably less than orequal to 87%, preferably less than or equal to 84.9%, preferably lessthan or equal to 82%, preferably less than or equal to 79.9%, preferablyless than or equal to 77%, preferably less than or equal to 74.9%,preferably less than or equal to 72% by weight of the composition of thepresent invention.

The composition of the present invention may also includepharmaceutically acceptable adjuvants for the treatment of skin lesions,such as coal tar and salicylic acid.

By the term “pharmaceutical active agent” we include any compound,including pharmaceutical acceptable derivatives such as a salt, solvateand pro-drug and any composition which may be used for the curativeand/or prophylactic treatment of a medical condition of a human oranimal. Preferably, the pharmaceutical active agent possessesantibacterial, antiviral and/or antifungal activity. More preferably,the pharmaceutical active agent comprises an antibacterial agent.

Suitably, the pharmaceutical active agent may be in the form of aliquid, gel or powder. Preferably, the pharmaceutical active agent is inthe form of a solid, particularly a powder, especially a powder that isinsoluble in typical pharmaceutical acceptable diluents, such as wateror alcohols.

Preferred antibacterial agents include antibiotic zeolites,chlorohexidine, polymyxin B sulphate, benzachromium chloride,benzamycin, clindamycin, erythromycin, tetracycline, mupirocin,bacitracin zinc and neomycin sulphate. Especially preferredantibacterial agents include antibiotic zeolites.

Preferred antibiotic zeolites include those in which theion-exchangeable ions of the zeolite such as sodium ions, potassiumions, calcium ions, magnesium ions and iron ions have been partially orcompletely ion-exchanged with antibiotic ions. Examples of suitableantibiotic ions include silver, copper, zinc, mercury, tin, lead,bismuth, cadmium, chromium and thallium ions. Preferred antibiotic metalions are silver, copper and zinc ions. These ions may be used alone orin combination. A particularly preferred antibiotic ion is silver.

Either natural or synthetic zeolites may be used as the “zeolitecomponent”. Examples of such zeolites are disclosed in U.S. Pat. No.5,556,699 which is incorporated herein by reference. Methods forpreparing the antibiotic zeolites for use in the composition of thepresent invention may be prepared by techniques well known to thoseskilled in the art, for example, as disclosed in U.S. Pat. No.5,556,699.

Preferably, the antibiotic metal ions are present in the zeolite in anamount of greater than or equal to 0.1%, preferably greater than orequal to 0.25%, more preferably greater than or equal to 0.75%, mostpreferably greater than or equal to 1% by weight of the zeolite.Preferably, the antibiotic metal ions in the zeolite is present in anamount of less than or equal to 15%, more preferably less than or equalto 10%, most preferably less than or equal to 5% by weight of thezeolite. By the term % by weight of the zeolite we mean expressed interms of the weight of the zeolite weighed after drying at a temperature110° C.

Preferably, the pharmaceutical active agent is present in an amount ofless than or equal to 50%, more preferably less than or equal to 30%,more preferably less than or equal to 10%, most preferably less than orequal to 3% by weight of the composition. Preferably, the pharmaceuticalactive agent is present in an amount of greater than or equal to 0.1%,more preferably greater than or equal to 0.5%, especially greater thanor equal to 1.0% by weight of the composition.

It will be appreciated by those skilled in the art that althoughantibiotic zeolites possess suitable antibiotic activity they typicallyrequire complex formulations in order to make them suitable forapplication, particularly topical application, to a target tissue.Surprisingly, it has been found that an antibiotic zeolite may beincorporated into the blend of the non-volatile silicone fluid and fumedsilica blend, with or without a diluent as described hereinafter,without the need for further complicated processing techniques.Moreover, the resultant composition of the present invention comprisingthe antibiotic zeolite may exhibit enhanced antibacterial activitycompared with the antibiotic zeolite alone.

Conveniently, the composition of the present invention may be regardedas a dual-purpose composition, as it may be employed for theprophylactic and/or reduction in scar tissue as well as the prophylacticand/or reduction of infection.

Preferably, the composition of the present invention further includes adiluent.

By the term “diluent” we include a vehicle that dissolves or dispersesthe non-volatile silicone fluid and fumed silica blend and thus reducesthe viscosity of the blend. Preferably the diluent is a volatilediluent. The volatile diluent preferably evaporates at normal bodytemperature (i.e. up to and including 38° C.) and atmospheric pressure.More preferably, the volatile diluent evaporates at room temperature(i.e. up to and including 25° C.) and atmospheric pressure.

Suitably, the volatile diluent exhibits appreciable vapour pressure atambient temperature. Preferably, the volatile diluent exhibits a heat ofvaporization at 25° C. of greater than or equal to 50 kJkg⁻¹, morepreferably greater than or equal to 75 kJkg⁻¹, even more preferablygreater than or equal to 100 kJkg⁻¹, most preferably greater than orequal to 125 kJkg⁻¹. Preferably, the volatile diluent exhibits a heat ofvaporization at 25° C. of less than or equal to 275 kJkg⁻¹, morepreferably less than or equal to 250 kJkg⁻¹, even more preferably lessthan or equal to 225 kJkg⁻¹, most preferably less than or equal to 200kJkg⁻¹.

Suitably, the volatile diluent exhibits a low viscosity when measured at25° C. The viscosity of the volatile diluent may be measured using aglass capillary viscometer such as a Ubbelohde available from FisherScientific Co., Pittsburgh, Pa., USA, employing test method ASTM D-445,IP71.

Preferably, the volatile diluent has a kinematic viscosity of greaterthan or equal to 0.5 mm²s⁻¹, more preferably greater than or equal to 2mm²s⁻¹, particularly greater than or equal to 3 mm²s⁻¹ when measured inaccordance with the above method. Preferably, the volatile diluent has aviscosity of less than or equal to 10 mm²s⁻¹, more preferably less thanor equal to 9 mm²s⁻¹, particularly less than or equal to 8 mm²s⁻¹ at 25°C. when measured in accordance with the above method.

Preferably, the diluent is a silicone fluid (such as a liquid) as theseare typically compatible with the non-volatile silicone fluid.Preferably, the volatile diluent is a volatile silicone fluid. Suitably,the volatile silicone fluid comprises a silicone polymer, particularly acyclomethicone silicone polymer. Preferred silicone polymers areselected from polydimethyl-cyclosiloxane, polymethyldisiloxane,octamethylcyclo-tetrasiloxane, hexamethyldisiloxane,dimethylcyclo-siloxane, dodecamethylcyclohexasiloxane,decamethylcyclo-tetrasiloxane or octamethyltrisiloxane or a mixturethereof.

Examples of suitable volatile silicone fluids are Dow-Corning 244 whichcomprises a cyclomethicone octamethylcyclotetrasiloxane, Dow-Corning 245which comprises a cyclomethicone decamethylcyclopentasiloxane DowCorning 246 which comprises a cyclomethicone dodecamethylcyclohexasiloxane and Dow Corning 345 which comprises a cyclomethiconedecamethylcyclopentasiloxane.

Mixtures of volatile silicone fluids may also be used to alter the rateof volatilization if desired. The volatile component may be added to themixture of non-volatile silicone fluid and fumed silica in anyproportion required to reduce the viscosity to an easy to apply oil orlight grease. At very high dilution, for example if 1 part by weight ofa blend of non-volatile silicone fluid and fumed silica is added to 1000parts by weight of the volatile diluent, then the product can be appliedas a mobile fluid with a suitable applicator, such as a roll-onapplicator, or even as a spray from a spray bottle. At the otherextreme, as little as 1 part by weight of the volatile diluent may beadded to 99 parts by weight of the non-volatile silicone and fumedsilica blends to produce a more viscous composition to assist in itsapplication.

Suitably, when present, the diluent is present at greater than or equalto 1%, preferably greater than or equal to 5%, preferably greater thanor equal to 10%, even more preferably greater than or equal to 15%, evenmore preferably greater than or equal to 20%, most preferably greaterthan or equal to 25% by weight, even more preferably greater than orequal to 30% by weight, most preferably greater than or equal to 35% byweight based on the total weight of the composition of the presentinvention. Suitably, when present, the diluent is present at less thanor equal to 99.9%, preferably less than or equal to 75%, even morepreferably less than or equal to 50% by weight based on the total weightof the composition of the present invention.

Suitably, when a diluent is included in the composition of the presentinvention, then the diluent may form substantially the balance of thecomposition of the present invention.

Suitably, when a diluent is included in the composition of the presentinvention, the non-volatile silicone fluid as described herein ispresent in an amount of greater than or equal to 20% by weight, morepreferably greater than or equal to 25% by weight, even more preferablygreater than or equal to 30% by weight, most preferably greater than orequal to 35% by weight based on the total weight of the composition ofthe present invention. Suitably, when a diluent is included in thecomposition of the present invention, the non-volatile silicone fluid asdescribed herein is present in an amount of less than or equal to 65% byweight, more preferably less than or equal to 60% by weight, even morepreferably less than or equal to 55% by weight based on the total weightof the composition of the present invention.

For the avoidance of doubt, when a diluent is included in thecomposition of the present invention, the amount of pharmaceuticalactive agent and fumed silica present in the composition is preferablywithin the preferred ranges as defined hereinbefore.

It will be appreciated that a volatile diluent may be employed insteadof or in conjunction with a non-volatile diluent so that the totalamount of diluent in the composition of the present invention is withinthe aforementioned stated ranges.

Suitably, the blend of the non-volatile silicone fluid and fumed silicahas a higher viscosity than the composition of the present invention andthe diluent i.e. a composition comprising the blend of the non-volatilesilicone fluid and fumed silica, the diluent and the pharmaceuticalactive agent. Consequently, a composition of the present inventionincluding the diluent may be prepared in the form of a spreadable cream,gel, oil or light grease which can be applied to a wound withoutproducing further injury of discomfort. Suitably, if a volatile diluentis employed in the composition of the present invention, after the blendis in place on the wound, evaporation of the volatile diluent therefrom,produces a resultant composition typically having an increased viscositythat is substantially equivalent to that of the blend of thenon-volatile silicone fluid and fumed silica alone. In other words, acoating having a viscosity of a stiff cream or grease may be formed froma spreadable cream, thereby providing increased wound adhesion and smearproofing, without producing further damage to the wound or undue painand discomfort during application. Furthermore, upon evaporation of thevolatile diluent the pharmaceutical active agent typically becomessequestered within the composition of the present invention i.e. theactive agent is retained by the composition and delivered topicallytherefrom to the target tissue.

It will be appreciated by those skilled in the art that the consistencyof the blend of the non-volatile silicone fluid and fumed silica may beadjusted by varying the quantity of the diluent present therein.Consequently the composition of the present invention including thediluent may be in the form of films and sheets, as well as a spreadablecream, gel, oil or light grease. Typically, the physical and chemicalproperties of the residual non-volatile silicone fluid and fumed silicablend and pharmaceutical active agent are unaltered after evaporation ofthe volatile diluent. However, it will be appreciated, particularly forhighly viscous silicone fluid and fumed silica blends, that traces ofthe volatile diluent may remain in the composition after applicationwhich may eventually be driven off by body heat.

Preferably, the composition of the present invention is in the form of agel or cream. Typically, when a volatile diluent is employed thisprovides a balance of residual durability of the ultimate compositionafter evaporation of the volatile diluent and ease of applicability.

Preferably, the composition of the present invention including a diluent(e.g. fumed silica, non-volatile silicone fluid, diluent andpharmaceutical active agent) has a viscosity of greater than or equal to1,000 centistokes, preferably greater than or equal to 5,000centistokes, more preferably greater than or equal to 10,000 centistokeswhen measured using a glass capillary viscometer using test method ASTMD-445, IP71 at 25° C. Preferably, the composition of the presentinvention including a diluent has a viscosity of less than or equal to25,000 centistokes, more preferably less than or equal to 22,000centistokes, most preferably less than or equal to 20,000 centistokes at25° C. when measured using a glass capillary viscometer using testmethod ASTM D-445, IP71.

Preferably, the composition of the present invention not including adiluent or the resultant composition formed after evaporation of avolatile diluent from the composition of the present invention includinga diluent (i.e. after application) has a viscosity of greater than orequal to 27,000 centistokes, more preferably greater than or equal to30,000 centistokes when measured at 25° C. using a glass capillaryviscometer using test method ASTM D-445, IP71 at 25° C. Preferably, thecomposition of the present invention not including a diluent or theresultant composition formed after evaporation of a volatile diluentfrom the composition of the present invention including a diluent has aviscosity of less than or equal to 45,000 centistokes, more preferablyless than or equal to 40,000 centistokes, most preferably less than orequal to 35,000 centistokes after evaporation of the volatile diluentwhen measured using a glass capillary viscometer using test method ASTMD-445, IP71 at 25° C.

Conveniently, the composition of the present invention including avolatile diluent (e.g. fumed silica, non-volatile silicone fluid,volatile diluent and pharmaceutical active agent) having an initialspecific viscosity within the aforementioned limits typically attainsthe resultant desired final viscosity (i.e. after evaporation of thevolatile diluent therefrom) by the application of body heat only.Conveniently, such a composition may be considered as “self-drying”following application to a target tissue site.

Suitably, a composition of the present invention including a volatilediluent in the form of a gel/cream having an initial viscosity of about15,000 to 20,000 centistokes at 25° C. (ASTM D-445, IP71) produces aresultant composition having a viscosity of about 30,000 to 35,000centistokes at 25° C. (ASTM D-445, IP71) in less than or equal to 20minutes, more preferably less than or equal to 18 minutes, even morepreferably less than or equal to 15 minutes following application of thecomposition to a target tissue site (i.e. when the composition issubjected to a temperature of approximately 38° C.). Suitably, acomposition of the present invention including a volatile diluent in theform of a gel/cream having an initial viscosity of about 15,000 to20,000 centistokes at 25° C. (ASTM D-445, IP71) produces a resultantcomposition having a viscosity of about 30,000 to 35,000 centistokes at25° C. (ASTM D-445, IP71) in greater than 10 minutes, more preferablygreater than or equal to 12 minutes following application of thecomposition to the target tissue site (i.e. when the composition issubjected to a temperature of approximately 38° C.).

A highly preferred composition of the present invention including adiluent comprises:

1 to 5% by weight fumed silica as defined herein;

35 to 65% by weight non-volatile silicone fluid as defined herein;

25 to 65% by weight volatile diluent as defined herein; and

1 to 5% by weight of a pharmaceutical active agent as defined herein,

wherein the component parts of the composition total 100% by weight.

Suitably, the composition of the present invention is suitable for usein medicine, particularly for the therapeutic, curative and/orprophylactic treatment of a medical condition for which the topicalapplication of the composition is indicated. Suitable medical conditionsinclude reducing and/or preventing scarring, ameliorating existingscars, reducing and/or preventing infection of a target tissue, such asa cut, wound or skin lesion, by a pathogen, such as bacteria, virusesand fungi. Furthermore, the composition of the present invention may besuitable for use in the therapeutic, curative and/or prophylactictreatment of eczema, psoriasis and dermatitis. Preferably, thepharmaceutical active agent possesses antibacterial, antiviral and/orantifungal activity, most preferably the pharmaceutical agent possessantibacterial activity, most preferably the pharmaceutical agent possessantibacterial activity.

According to a further aspect, the present invention provides a methodfor delivering a pharmaceutical active agent as defined hereinbefore toa target tissue by administering a composition of the present inventionas defined hereinbefore to the target tissue. Suitably, the targettissue comprises a wound, such as a skin lesion, cut or a scar.Preferably, the composition is administered topically to the targettissue.

According to yet a further aspect, the present invention provides amethod for reducing and/or preventing scarring, particularlyhypertrophic or keloid scars, comprising administering a composition ofthe present invention as defined hereinbefore to a wound, cut, skinlesion or a scar. Conveniently, the composition of the present inventionmay be administered topically to the target tissue site. Suitably, thepresent invention provides a wound dressing comprising a composition ofthe present invention as defined hereinbefore. Suitably, the wounddressing may be in a form as described herein e.g. gel, stiff cream,film etc.

Conveniently, the composition of the present invention may ameliorate orreduce existing scars when applied thereto.

According to a further aspect, the present invention provides a methodof manufacturing a composition of the present invention as definedherein, comprising contacting a pharmaceutical active agent as definedherein with a non-volatile silicone fluid and fumed silica as definedherein. Preferably, the pharmaceutical active agent is mixed with ablend of the non-volatile silicone fluid and fumed silica. Preferably, adiluent, particularly a volatile diluent, as defined hereinbefore isalso added to the composition of the present invention.

Preferably, the compositions of the present invention are prepared bymethods well known to those skilled in the art for example by usingstirrers, blenders, mills and the like and other methods suitable forblending silicone oils and fumed silica. In addition, pressure vesselsand condensing systems may be used to retain the volatile diluent if oneis included in the composition of the present invention. Suitably, thenon-volatile silicone fluid and fumed silica blend is initially preparedand then admixed with the diluent, if one is included, and thepharmaceutical active agent. Alternatively, the blend of thenon-volatile silicone fluid and fumed silica and a diluent may be formedin one stage and the pharmaceutical active agent added thereto. It willbe appreciated by those skilled in the art that the pharmaceuticalactive agent may be added at any stage of the preparation of thecomposition of the present invention.

Typically, when the pharmaceutical active agent represents an antibioticzeolite a masterbatch comprising the pharmaceutical active agent, themixture of a blend of non-volatile silicone fluid and fumed silica, andoptionally the diluent as described hereinbefore, is initially prepared.Suitably, the masterbatch includes the pharmaceutical active agent at20% by weight of the masterbatch. The masterbatch may then be dilutedwith the mixture of the blend of non-volatile silicone fluid and fumedsilica and/or the diluent to form a composition of the present inventionhaving the desired concentration of the pharmaceutical active agent asdescribed hereinbefore (typically 1 to 5 wt % of the composition for anantibiotic zeolite). Advantageously, such a processing technique mayensure correct dispersion of the antibiotic zeolite in the blend ofnon-volatile silicone fluid and fumed silica, and optionally thediluent, whilst minimizing the agglomerization of the antibioticzeolite, thereby resulting in an increased antibiotic activity of thecomposition of the present invention.

Alternatively, or additionally, a dispersant such as magnesium stearate,may be added to the masterbatch to promote dispersion of the antibioticzeolite within the composition of the present invention. Typically, ananhydrous dispersant is mixed with the anhydrous antibiotic zeolitebefore compounding. Preferably, 10% by weight of the dispersant isincluded. The antibiotic zeolite/dispersant mixture may then be used toform a masterbatch as described hereinbefore. Preferably, particularlyin the case of an antibiotic zeolite, the compositions of the presentinvention are prepared under anhydrous conditions as the inclusion ofwater in the compositions of the present invention may promotediscoloration and agglomerization of the pharmaceutical active agent,thereby resulting in decreased efficiency of the composition.

According to a further aspect, the present invention provides a methodfor treating a wound comprising applying composition of the presentinvention to a wound.

According to a further aspect, the present invention provides a topicalpharmaceutical delivery system comprising a composition of the presentinvention.

According to a further aspect, the present invention provides a wounddressing comprising a composition of the present invention.Conveniently, the wound dressing may deliver a pharmaceutical activeagent to the target tissue and/or prevent, reduce or ameliorate scarringat the target tissue site.

It will be appreciated by those skilled in the art, that thecompositions of the present invention may be administered by non-medicalprofessional staff. Suitably, the compositions of the present inventionare applied to the target tissue by means well known to those skilled inthe art, such as application with a spatula, a roll-on or spray typeapplicator

The invention will now be described by way of the following non-limitingexamples.

The following raw materials were used:

Agion™ an antibiotic zeolite, in which the ion-exchangeable ions of thezeolite have been partially or fully exchanged with silver ions,supplied by Agion Technologies of 60 Audubon Road, Wakefield, Mass.01880, USA;

Dow Corning 200 having a viscosity at 25° C. of about 30,000 centistokes(non-volatile silicone fluid);

Dow Corning 245 comprising polydimethylcyclosiloxane having a viscosityof 4 mm²s⁻¹ at 25° C. (volatile diluent); and

Aerosil™ fumed silica.

EXAMPLE 1 Preparation of a Composition of the Present Invention

A masterbatch comprising 20 weight percent Agion™ and the balance of themasterbatch (80 wt %) comprising a mixture of Aerosil 200, Dow Corning200 and Dow Corning 245 (3% by weight Aerosil 200: 50% by weight DowCorning 200: 47% by weight Dow Corning 245) was prepared by adding theAgion™ powder to a blend of the non-volatile silicone fluid, fumedsilica and volatile silicone diluent. The masterbatch was stirred with aJH Day Pony Mixer at ambient temperature, under anhydrous conditions,for up to 2 hours to effect dispersion of the Agion™ powder. Themasterbatch was then diluted with the desired amount of the mixture ofAerosil 200, Dow Corning 200 and Dow Corning 245 (3% by weight: 50% byweight: 47% by weight) to form the following compositions of the presentinvention in the form of a gel having a viscosity of 19,000 to 21,000centistokes at 25° C. when measured by a glass capillary viscometer bytest method ASTM D-445, IP71.

Agion ™ Aerosil:Dow Corning 200:Dow % by wt of the Corning 245 (3:50:47)composition % by weight of the composition Example 1a 1 99 Example 1b 298 Example 1c 5 95

EXAMPLE 2 Antibacterial Activity

Antibacterial activity against staphylococcus aureus was determined byincubating each of the compositions of Example 1a, Example 1b andExample 1c with the bacterial strain, staphylococcus aureus on a 2×2inch agar plate, for 24 hours in the presence of oxygen. A compositioncomprising a mixture of 3% by weight Aerosil 200, 50% by weight DowCorning 200 and 47% by weight Dow Corning 245 (i.e. without Agion™) wasused as the control.

The results as shown in Table 1 demonstrate the enhanced antibacterialactivity of the compositions of the present invention. The controlsample and the assay alone (i.e. the assay not including a controlsample) exhibited an increase in bacterial activity.

TABLE 1 Organism count (CFU/ml) Sample Zero Contact 24 Hours PercentIdentification Time Contact Time Reduction (%) ASSAY 3.60 × 10⁴ 4.50 ×10⁴ NO REDUCTION CONTROL 3.60 × 10⁴ 1.01 × 10⁵ NO REDUCTION COMPOSITIONOF 3.60 × 10⁴ <10* 99.99% THE INVENTION WITH 1% AGION COMPOSITION OF3.60 × 10⁴ <10* 99.99% THE INVENTION WITH 2% AGION COMPOSITION OF 3.60 ×10⁴ <10* 99.99% THE INVENTION WITH 5% AGION NOTE: *<10 = Limit ofdetection of assay

EXAMPLE 3 In-Vivo Wand Healing/Antibacterial Activity

Three human volunteers having wounds which had started to develop intokeloid scars were selected.

The composition of Example 1a (2 g) was spread over the scar of thefirst volunteer and the composition immobilised until sufficientvolatile diluent had evaporated therefrom (approx. 15 minutes) so thatthe resulting composition adhered to the tissue site.

A control composition (2 g) comprising a mixture of 3% by weight Aerosil200, 50% by weight Dow Corning and 47% by weight Dow Corning 245 wasspread over the scar of the 20 second volunteer and the compositionimmobilised until sufficient volatile diluent had evaporated therefrom(approx. 15 minutes) so that the resulting composition adhered to thetissue site.

Agion™ powder alone (40 mg) was placed over the scar of the thirdvolunteer and the powder immobilised on the tissue site with atransparent adhesive plaster.

Each of the patients were monitored over a 1 month period and thereduction in redness (representing a decrease in infection) andflattening of the scar (representing scar amelioration and/or preventionand/or reduction) was recorded. The results are presented in Table 2below.

TABLE 2 Sample Reduction in Redness Flattening of Scars Example 1aImmediate reduction in Steady reduction in level redness after 2 days,of scar. After one month further decrease in scar showing visible signsredness occurred. of disappearing. Control Minor decrease in rednessReduction in level of scar after 1 month. after 1 month but not assignificant as Example 1a as scar present after 1 month and no signs ofscar disappearing. Agion ™ alone Reduction in redness A scar developed.observed after 4 days.

The results demonstrate that the composition of the present inventionnot only reduces the redness of the scar (indicative of antibacterialactivity) but also prevents and/or ameliorates scarring. Moreover, thereappears to be a synergistic effect of antibacterial and/or scar reducingeffects employing a combination of the antibiotic zeolite and thenon-volatile silicone fluid/fumed silica mixture compared with employingthe component parts of the composition of the present invention.

EXAMPLE 4

The following compositions as listed in Table 3 were prepared inaccordance with Example 1 above except the Agion™ antibiotic zeolite wasreplaced with the appropriate pharmaceutical active agent.

TABLE 3 Pharmaceutical Aerosil:Dow Corning 200:Dow Active Agent Corning245 (3:50:47) (% by weight of the (% by weight of the composition)composition) Example 4a Chlorohexidine acetate 98% by wt (2% by wt)Example 4b Benzamycin (3% by wt) 97% by wt Example 4c Erythromycin (3%by wt) 97% by wt

EXAMPLE 5

The following composition comprising 2% by weight Agion™ and the balancecomprising a mixture of 3% by weight Aerosil and 97% by weight DowCorning 200 was prepared in accordance with Example 1 above. Theresultant composition was in the form of a viscous gel having aviscosity of approximately 28,000 to 30,000 centistokes at 25° C. whenmeasured by a glass capillary viscometer by test method ASTM D-455,IP71.

The reader's attention is directed to all papers and documents which arefiled concurrently with or previous to this specification in connectionwith this application and which are open to public inspection with thisspecification, and the contents of all such papers and documents areincorporated herein by reference.

All of the features disclosed in this specification (including anyaccompanying claims, abstract and drawings), and/or all of the steps ofany method or process so disclosed, may be combined in any combination,except combinations where at least some of such features and/or stepsare mutually exclusive.

Each feature disclosed in this specification (including any accompanyingclaims, abstract and drawings), may be replaced by alternative featuresserving the same, equivalent or similar purpose, unless expressly statedotherwise. Thus, unless expressly stated otherwise, each featuredisclosed is one example only of a generic series of equivalent orsimilar features.

The invention is not restricted to the details of the foregoingembodiment(s). The invention extend to any novel one, or any novelcombination, of the features disclosed in this specification (includingany accompanying claims, abstract and drawings), or to any novel one, orany novel combination, of the steps of any method or process sodisclosed.

1. A wound dressing consisting of at least one non-volatile siliconefluid in admixture with fumed silica, one or more antibacterial activeagent, and at least one volatile diluent.
 2. The wound dressing of claim1, wherein said at least one non-volatile silicone fluid consists of asilicone polymer.
 3. The wound dressing of claim 1, wherein said atleast one non-volatile silicone fluid is present in an amount of greaterthan or equal to 20% by weight of the wound dressing.
 4. The wounddressing of claim 1, wherein the blend of said at least one non-volatilesilicone fluid and fumed silica consists of greater than or equal to 2%by weight fumed silica.
 5. The wound dressing of claim 1, wherein theblend of said at least one non-volatile silicone fluid and fumed silicaconsists of less than or equal to 12% by weight fumed silica.
 6. Thewound dressing of claim 1, wherein said one or more antibacterial activeagent is present in an amount of greater than or equal to 0.1% by weightof the wound dressing.
 7. The wound dressing of claim 1, wherein saidone or more antibacterial active agent is present in an amount of lessthan or equal to 50% by weight of the wound dressing.
 8. The wounddressing of claim 1, wherein at least one of said one or moreantibacterial active agent is in the form of a solid.
 9. The wounddressing of claim 1, wherein at least one of said one or moreantibacterial active agent is an antibiotic zeolite.
 10. The wounddressing of claim 9, wherein the antibiotic zeolite consists ofion-exchangeable ions which have been totally or partially ion-exchangedwith an antibiotic metal ion selected from the group consisting ofsilver ions, copper ions, zinc ions and a mixture thereof.
 11. The wounddressing of claim 10, wherein the antibiotic metal ions in the zeoliteare present in an amount of greater than or equal to 0.1% by weightbased on the weight of the zeolite.
 12. The wound dressing of claim 10,wherein the antibiotic metal ions in the zeolite are present in anamount of less than or equal to 15% by weight based on the weight of thezeolite.
 13. The wound dressing of claim 1, wherein said at least onevolatile diluent consists of a volatile silicone fluid.
 14. The wounddressing of claim 1, wherein said at least one diluent is present in anamount of greater than 1% by weight of the wound dressing.
 15. The wounddressing of claim 1, wherein the viscosity of said one or more diluentis less than or equal to 10 mm²s⁻¹ at 25° C. when measured by testmethod ASTM D-455.
 16. The wound dressing of claim 1, wherein uponevaporation of said at least one volatile diluent from the wounddressing, the resultant wound dressing has a higher viscosity.
 17. Thewound dressing of claim 1, wherein said at least one non-volatilesilicone fluid has a viscosity of less than or equal to 200,000centistokes when measured at 25° C.
 18. The wound dressing of claim 1,wherein the wound dressing is in the form of a spreadable cream, gel,oil, light grease or mobile spray on fluid.
 19. The wound dressing ofclaim 1, consisting of: 1 to 5% by weight fumed silica; 35 to 65% byweight non-volatile silicone fluid; 25 to 65% by weight volatilediluent; and 1 to 5% by weight of an antibacterial active agent, whereinthe component parts of the wound dressing total 100% by weight.
 20. Amethod of manufacturing the wound dressing of claim 1 consisting ofcontacting an antibacterial active agent with a mixture of anon-volatile silicone fluid and fumed silica.
 21. A method for theprophylactic treatment, therapeutic treatment or combination thereof ofa tissue site infected by a pathogen, the method consisting of applyingthe wound dressing of claim 1 to the tissue site.
 22. A method for theprophylactic treatment, therapeutic treatment or combination thereof ofa scar consisting of applying the wound dressing of claim 1 to saidscar.
 23. A method for delivering a pharmaceutical active agent to atarget tissue, the method consisting of administering the wound dressingof claim 1 to the target tissue.
 24. The method of claim 23, wherein thewound dressing is applied topically to the target tissue.
 25. A methodfor reducing scarring, preventing scarring or a combination thereofconsisting of administering the wound dressing of claim 1 to a tissuesite.
 26. A method for treating a wound consisting of applying the wounddressing of claim 1 to the wound.
 27. A topical pharmaceutical deliverysystem consisting of the wound dressing of claim
 1. 28. An applicatorcomprising a reservoir consisting of the wound dressing of claim 1, anda dispenser in fluid communication with the reservoir for dispensing thewound dressing from the reservoir.
 29. The applicator of claim 28wherein the dispenser consists of a spray, a roller ball, or a spatula.30. The wound dressing of claim 2, wherein the silicone polymer consistsof a linear dimethicone.
 31. The wound dressing of claim 2, wherein thenon-volatile silicone fluid is present in an amount of greater than orequal to 20% by weight of the wound dressing.
 32. The wound dressing ofclaim 8, wherein the solid consists of a powder.
 33. The method of claim21, wherein the pathogen is bacteria or viruses.
 34. The method for theprophylactic treatment, therapeutic treatment or combination thereof ofa scar as claimed in claim 22, wherein the wound dressing reduces scars,prevents scars or a combination thereof within a time of one month orless.
 35. A method for reducing, preventing or ameliorating scarring ofdamaged tissue consisting of applying the wound dressing as defined inclaim
 1. 36. A wound dressing consisting of at least one non-volatilesilicone fluid in admixture with fumed silica, one or more antibacterialactive agent, and at least one volatile diluent, said wound dressingbeing capable of ameliorating, preventing, or reversing the formation ofscarring at a tissue site when said wound dressing is made to contactthe site.
 37. A method of manufacturing the wound dressing of claim 1consisting of contacting an antibacterial active agent with a mixture ofa non-volatile silicone fluid and fumed silica, and adding a diluent tothe mixture thereof.